The year 2011 marked the 30th anniversary of the HIV/AIDS pandemic with 25 million AIDS-related deaths world-wide and 33 million people currently infected with the virus. The course of the disease changed dramatically with the advent of antiretroviral drugs, which target HIV-1 enzymes critical to the viral life cycle as well as fusion of the virus with the host cell. While cocktails of these drugs have extended the life expectancy of infected individuals, they do not clear the virus and require life-long administration. Chronic drug therapy, coupled with the remarkable mutational capacity of HIV-1, continues to drive drug resistance. The emergence of multi-drug resistant strains of HIV-1, together with uncertain prospects for an effective vaccine, underscores the urgent need for new antiretrovirals with mechanisms of action complementary to existing agents.